Anti-migration features and geometry for a shape memory polymer stent

ABSTRACT

A radially-expandable stent for implantation in a bodily passageway, being expandable from an initial unexpanded state to an expanded state, having an outer surface with a geometric pattern covering said outer surface to minimize migration after implantation is provided. Also provided is a method of manufacturing such a stent.

CROSS-REFERENCE TO RELATED APPLICATION

This patent application claims priority to and the benefit of U.S.Provisional Patent Application No. 60/934,607 filed Jun. 13, 2007 whichis hereby incorporated by reference herein.

FIELD OF THE INVENTION

This invention relates to a shape memory stent having features andgeometry on the stent's outer surface specifically adapted to minimizemigration of the stent once it has been implanted and a method ofmanufacturing thereof.

BACKGROUND OF THE INVENTION

Stents are often used in the gastrointestinal tract to treat malignantor benign strictures as palliative or supporting treatment tochemotherapy or surgery. With biliary stent applications, plastic stentsare often used. Plastic stents are typically have an outer diameter of3.5 mm and an inner diameter of 2.5 mm and need to be exchangedrelatively often (e.g., every three months) due to occlusion from bile.However, an advantage of plastic stents, besides their lower cost, isthat their relative small size enables their use within and endoscopyinstrument or endoscope. Conversely, self expanding metal stents (SEMS),are also useable and tend to have a longer patency than plastic stentsbecause of their larger diameters, typically 8-10 mm, and having afurther advantage that metal stents are collapsible from a larger tosmaller diameter and may fit within and endoscope, and then expanded toa larger diameter. However, plastic stents are removable, whereas, metalstents generally are not. Common practice calls for removing stents whentreatment of benign strictures is completed.

Accordingly, metal stents are generally restricted to use wheremalignant, not benign, strictures are present. In addition to theproblems of permanency of metal stents, their costs are 10 to 15 timeshigher than plastic stents.

Because of inherent material deficiencies, plastic stents cannot be madeand reliably used, having larger diameters that collapse down to smalldiameters and retaining good compression resistance as with selfexpanding metal stents. A need had developed for a stent having innerand outer diameters in a range similar to metal stents, e.g., 8-10 mm,yet have a low entry profile, and also be removable. SMP stents satisfythis need with SMP stents both being useable at the relatively largediameters, thereby providing good patency, and being removable, thusallowing for use with both benign and malignant applications.Additionally, a major benefit of SMP stents is that they are collapsibleto a small diameter for insertion into a lumen of a patient, but canthen be expanded like a metal stent once inside a patients lumen andthen have the functional characteristics of a plastic stent.

SMP stents are preferably formable as tubular structures (which may beetched) or as coiled structures resembling coil springs. With eitherconfiguration, a straight, generally cylindrical shape may not bedesired, due to the possibility of migration within a bodily passageway.A method has been developed of pre-forming SMP stents with one or bothends flared, with the SMP stents recovering this configuration in vivoat the point of implantation. However, in preparing the SMP stents, thestents are initially pre-formed with the flared-end configuration andthen contracted to a minimized diameter for insertion into a catheter(in being readied for implantation). The contracted profile of the SMPstents resembles proportionately the profile of the fully-expandedstents, with the ends being likewise flared. With the smallest possibleprofile being sought for insertion into a patient, the flared-endconfigurations of the contracted SMP stents may be undesirable. Anothermethod of minimizing migration of an SNIP stent is to form the stentwith the inclusion of a shaped or textured outer surface, whichtherefore provides mechanical connection between the stent and theluminal surface of the vessel where the stent is implanted.

SUMMARY OF THE INVENTION

The present invention may utilize a modification of the stent's outersurface with features such as coils, rings, mesh and other surfaces toprovide a mechanical bonding surface. One embodiment of the presentinvention therefore relates to a radially-expandable implant forimplantation in a bodily passageway, being at least partially expandablefrom an initial unexpanded state to an expanded state, having an outersurface with a geometric pattern covering said outer surface to minimizemigration after implantation.

In another embodiment, the invention comprises a geometric cross sectionthat interacts with a body lumen to limit migration of an implant. Forexample, in a round or square stent, the implant may have at least onesurface feature such as a protrusion from the outer wall formechanically interacting with the a body lumen. Alternately, the stentmay be of an undulating shape with directional surface features whichinhibit motion in one direction while allowingtransportability/flexibility in the other direction.

The stent of the current embodiment is useable in various bodilypassageways for implanting a stent, including the gastrointestinal tract(e.g., bile ducts, colon, duodenum), esophagus, trachea, urine tract(e.g., urethra, prostate) and vasculature (e.g., coronary blood vessels,peripheral blood vessels, intracranial blood vessels).

These and other features will be better understood through a study ofthe following detailed description and accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A, B, and C are a schematic of an assembly including a mold andstent in accordance with the present invention having a particularexternally extending outer geometry;

FIGS. 2A, B, and C are a schematic of an assembly including a mold andstent in accordance with the present invention having a particularexternally extending outer geometry;

FIGS. 3A, B, and C are a schematic of an assembly including a mold andstent in accordance with the present invention having a particularexternally extending outer geometry;

FIGS. 4A, B, and C are a schematic of an assembly including a mold andstent in accordance with the present invention having a particularexternally extending outer geometry;

FIG. 5 depicts an alternate embodiment of the implant according to thepresent invention having circumferential sections of an externallyextending outer geometry;

FIG. 6 depicts an alternate embodiment of the implant according to thepresent invention having longitudinal sections of an externallyextending outer geometry; and

FIG. 7 depicts an alternate embodiment of the implant according to thepresent invention having discrete discontinuous sections of anexternally extending outer geometry.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with one embodiment of the present invention, the implantcomprising a stent can be manufactured by utilizing an injection moldingprocess. By utilizing this process, a particular surface geometry of thestent can be controlled by cutting the inverse geometric configurationinto the inner diameter of the mold. The inner surface of the mold cancontain any of various geometrical patterns such as a helical coil,mesh, rings or rough textured surface, as shown in the accompanyingfigures. Any change in geometry on the exterior wall of the implant mayminimize migration while preferably preventing tissue damage in situ orupon removal. Additionally one embodiment of the present inventionallows fluids from either the pancreatic duct or cystic duct to passbetween the wall of the bile duct and the outer surface of the stent,should the stent pass over these ducts.

In one embodiment, the invention comprises a stent and, more preferably,a stent suited for placement within the gastrointestinal tract of ananimal or human. In a further embodiment, the GI tract comprises thepancreatic duct, cystic duct or common bile duct. In yet a furtherembodiment, the outer surface of the implant comprises at least onesurface modification to assist in limiting the potential migration ofthe implant within the body lumen.

FIG. 1A illustrates a mold comprising a top portion 100 and a bottomportion 102. The top portion may comprise an inner and outer surface,wherein the inner surface may be adapted to receiving material for themanufacture of the stent according to the present invention. The stent104 may be formed as a hollow structure, which may be etched, or may beformed as a coiled structure resembling a coil spring. U.S. patentapplication Ser. No. 10/683,314, filed Oct. 10, 2003 (published Jan. 13,2005 as U.S. Publication No. 2005-0010275 A1), disclose suitablematerials and geometries for Shape Memory Polymer (hereinafter SMP)stents. The entire disclosures of U.S. patent application Ser. No.10/683,314 are incorporated by reference herein.

In one embodiment, the stent 104 comprises an SMP. Examples of SMP'sinclude polynorbornene and copolymers of polynorbornene, blends ofpolybornene with KRATON® (thermoplastic elastomer) and polyethylene,styrenic block copolymer elastomers (e.g., styrene-butadiene),polymethylmethacrylate (PMMA), polyethylene, polyurethane, polyisoprene,polycaprolactone and copolymers of polycaprolactone, polylactic acid(PLA) and copolymers of polyactic acid, polyglycolic acid (PGA) andcopolymers of polyglycolic acid, copolymers of PLA and PGA, polyenes,nylons, polycyclooctene (PCO), polyvinyl acetate (PVAc), polyvinylidenefluoride (PVDF), blends of polyvinyl acetate/polyvinylidine fluoride(PVAc/PVDF), blends of polymethylmethacrylate/polyvinylacetate/polyvinylidine fluoride (PVAc/PVDF/PMMA) and polyvinylchloride(PVC) and blends and/or combinations thereof.

The implant 104, comprising SMP, may be pre-formed to an initialdiameter and then may be heated, to a temperature that may be near orabove the melt or glass transition. It may then be mechanically deformedto a smaller, contracted profile, suitable for delivery into the body ofa patient. The implant 104 is cooled and for implantation may beassembled onto a catheter (not shown), or other delivery system anddelivered into the body of a patient. The implant may then be expandedwith application of heat to the melt or glass transition.

In some embodiments a, balloon may be used to expand a portion of theimplant 104 to a profile greater than the pre-formed reduced profile. Assuch, the implant 104 may be deformed in vivo at the point ofimplantation. The implant 104 may be pre-formed with a smaller overallprofile for implantation. In some embodiments, the implant 104 may bepre-formed with a geometric pattern on the outside surface of the stent.The pattern may become more prominent when the implant 104 is expandedto a final configuration. In the reduced profile of the implant 104 maybe minimized, yet some memory may be imparted to the s implant 104 toaid in formation of the geometric shape. In some embodiments, implant104 is not reduced in profile.

Additionally, a stent may be removable, through the use of SMP. Theimplant 104 may be manufactured as a small diameter and put on theballoon, and then expanded to a large diameter when implanted in thebody. Subsequently, the stent may be removed by reintroducing heat intothe stent, which will cause the stent to shrink to its original smallerdiameter, thus facilitating removal through a catheter, or endoscopyinstrument. Some implants may not be totally formed of SMP. SMP mayprovide a support structure or scaffold with another expandable materialcombined, or laid over or within the implant.

An SMP stent and a graft may be combined into a stent-graftendoprosthesis to combine the features and advantages of each. Forexample, tubular coverings have been provided on the inner and/or outersurfaces of stents to form stent-grafts. It is often desirable to use athin-walled graft or covering in the stent-graft endoprosthesis tominimize the profile of the endoprosthesis and to maximize the flow ofblood through the endoprosthesis. In such cases non-textile materials,such as polymeric tubes or sheets formed into tubes, are often used.

Expanded polytetrafluoroethylene or e-PTFE is one common polymericmaterial used as the graft portion or covering of a stent-graftendoprosthesis. Expanded polytetrafluoroethylene grafts, however, aresubject to plastic deformation, especially when, for example,compressing the stent-graft for loading into its delivery system,delivering the stent-graft through a highly tortuous bodily lumen and/orplacing or deploying the stent-graft at the target implant site. Suchplastic deformation may lead to the tearing of the ePTFE, leaving thestent-graft endoprosthesis prone to leakage of blood therethrough.Furthermore, plastic deformation of expanded polytetrafluoroethylenegrafts may lead to physical deformities in the graft, such as buckling,which is also undesirable because it may lead to poor blood flowpatterns.

Sheets or films of ePTFE have been used to cover or line stents. Forexample, U.S. Pat. Nos. 5,700,285 and 5,735,892 to Myers et al. describeoverlapping a sheet of ePTFE onto a stent to form a tubular graft. Thegraft is secured to the stent by an application of thermoplasticadhesive and heat treatment to melt the adhesive. A seam, which isformed where the sheet overlaps, is also sealed through the use of thethermoplastic adhesive.

In one embodiment, the stent may be manufactured by utilizing aninjection molding process. A desired surface geometry of the implant canbe controlled by cutting the inverse geometry into the inner surface ofa mold. SMP may be injected into the mold. An inner surface of this moldmay contain any of various geometrical patterns including a helicalcoils, meshs, rings or a rough textured surface; which will be furtherillustrated in FIGS. 1-4. Such geometries, or other patterns may permitbodily tissue such as a body lumen to engage in recesses of the pattern.This type of engagement may help minimize migration of the stent and mayreduce tissue damage. Furthermore, tissue damage may be reduced inrepository or removal procedures.

An alternate method of manufacturing implant 104 with a surfacemodification may include extruding the tubing to a constrained diameter.A reduced profile plug of SMP may be placed inside a mold. The plug maythen be expanded within a mold having a pattern. The mold may have exitpoints to permit flow of the SMP out of the mold as one manner tocontrol the volume of SMP within the mold.

In another alternate method of manufacture, the implant 104 may beformed by molding the exterior surface modification onto a separatelayer of material, such as for example a non-textile material. As usedherein, the term “non-textile” and its variants refer to a materialformed by casting, molding, spinning or extruding techniques to theexclusion of typical textile forming techniques, such as braiding,weaving, knitting and the like. Nonlimiting examples of useful polymericmaterials for the non-textile polymeric graft portions includepolyesters, polypropylenes, polyethylenes, polyurethanes,polynaphthalenes, polytetrafluoroethylenes, expandedpolytetrafluoroethylene, silicone, and combinations and copolymersthereof. Desirably, the polymeric material polytetrafluoroethylene(PTFE), including expanded polytetrafluoroethylene (ePTFE).

PTFE exhibits superior biocompatibility and low thrombogenicity, whichmakes it particularly useful as vascular graft material in the repair orreplacement of blood vessels or other bodily lumens. Desirably thenon-textile layer is a tubular structure manufactured from ePTFE. TheePTFE material has a fibrous state which is defined by interspaced nodesinterconnected by elongated fibrils. The space between the node surfacesthat is spanned by the fibrils is defined as the internodal distance.When the term expanded is used to describe PTFE, it is intended todescribe PTFE which has been stretched, in accordance with techniqueswhich increase the internodal distance and concomitantly porosity. Thestretching may be in uni-axially, bi-axially, or multi-axially. Thenodes are spaced apart by the stretched fibrils in the direction of theexpansion.

Desirably, the ePTFE material is a physically modified ePTFE tubularstructure having enhanced axial elongation and radial expansionproperties of up to about 2,000 percent by linear dimension, forexample, from about 100 percent by linear dimension to about 2,000percent by linear dimension, from about 100 percent by linear dimensionto about 600 percent by linear dimension, from about 600 percent bylinear dimension to about 2,000 percent by linear dimension, and thelike. Such expansion properties are provided as exemplarycharacteristics and are do not limit the extent of elongation in anymanner. Such physically modified ePTFE material may be made byreorienting the node and fibril structure through application a radiallyexpansive and longitudinally foreshortening force. The physicallymodified ePTFE tubular structure is able to be elongated or expanded andthen returned to its original state without an elastic force existingtherewithin. Additional details of the physically modified ePTFE andmethods for making the same can be found in U.S. Pat. No. 6,716,239, thecontents of which are incorporated by reference herein.

The non-textile, polymeric implant layer may be secured to a SMP implantscaffold structure 104 through any suitable means, including, withoutlimitation, lamination, such as heat and/or pressure lamination, and/oradhesive bonding. The bonding agent may include various biocompatible,elastomeric bonding agents such as urethanes,styrene/isobutylene/styrene block copolymers (SIBS), silicones, andcombinations thereof. Other similar materials are contemplated.Desirably, the bonding agent may include polycarbonate urethanes soldunder the trade name CORETHANE®. This urethane is provided as anadhesive solution with preferably 7.5% Corethane, 2.5 W30, indimethylacetamide (DMAc) solvent. Details of suitable bonding agents andmethods for bonding are further described in U.S. Patent ApplicationPublication Nos. 2003/0017775 A1 and 2004/0182511 A1, the contents ofwhich are incorporated herein by reference.

In another alternate method of manufacture, the implant 104 may beformed by attaching a first layer of non-textile material to theexterior of the SMP scaffold and second layer of non-textile material tothe exterior surface of the first layer of non-textile material. Thefirst and second layers may be of a non-textile polymeric material asdescribed above and attached to a scaffold as described above.Additionally, however, in this alternate embodiment, the second layermay have externally extending features which are created on the exteriorof the second layer after it is attached to the first layer. Theexternally extending features may be created by removing material fromthe second layer by any suitable method, for example by laser cutting,chemical etching, electrochemical etching, and the like.

FIG. 1 illustrates a mold top portion 100 and a bottom portion 102. Thetop portion 100 and bottom portion 102 may have an exterior 106 andinterior 108 surface. The interior 108 surface of both the top 100 andbottom 102 portions may be adapted to receive a shape memory polymermaterial for a molding process., FIG. 1A illustrates the interior 108surface of bottom portion 102 of a mold, wherein the mold comprises aninverse geometry textured surface or other surface modification. In oneembodiment a textured surface comprises a diagonal cross hatch pattern110, made up of overlapped rows 112 and 114 which are diagonallydisposed to each other. A recess may be formed in the mold between twosuccessive pairs of diagonally rows 112 and 114. As illustrated in FIG.1 C, a mold may be an inverse of the implant. The mold may compriserecesses which inversely results in a raised regions of the implant 104.In one embodiment the surface modifications comprise a pyramid-likeshape when the molding process is complete. Of course one skilled in theart will recognize the pattern described can be varied in various ways.For example, one variation may include changing the angle at which thediagonally disposed rows cross one another. Furthermore the depth of theraised region may be increased or decreased and the shape may bechanged. For example, the raised region may have a pointed shape oralternately a curved convex shape. Furthermore, the rough texturedsurface could be made of an entirely different shape not incorporatingthe diagonal rows or raised pyramid-like shaped regions. For example,the raised regions may have a hemispherical or other curved shape.

FIG. 2A illustrates a mold top portion 200 and a bottom portion 202. Thetop portion 200 and bottom portion 202 may have an exterior 206 andinterior 208 surface. An interior 208 surface of both the top 200 andbottom 202 portions may be adapted to receive a shape memory polymermaterial. FIG. 2B illustrates the interior 208 surface of bottom portion202 of the mold. In one embodiment, the mold may comprise the inversegeometry of a rings 210. In the particular embodiment depicted, therings may comprise a pattern of annular rings 210 disposed about thecircumference of the mold interior 208 perpendicular to the longitudinalaxis of the mold. rings 210 may have a depth 214, longitudinal distance216 and longitudinal separation distance 218.

FIG. 2C illustrates a mold being an inverse of an implant and furthercomprising annular rings. Annular rings may result results in a raisedpattern 212. One skilled in the art will recognized the patterndescribed can be varied by changing the depth 214, longitudinal length216 of the annular rings 210, or the spacing 218 between each ringangle. Variations may include varying the longitudinal distance of theannual rings to make them shorter or longer in accordance with the needsof the particular application. Likewise, the longitudinal distancebetween each ring may be varied, such that the rings may be separated bya longer or shorter distance. Furthermore, the ring shape could bevaried such that the rings are not aligned with the longitudinal axis ofthe implant. For example, the rings may be arranged at an angle to thelongitudinal axis of the implant wherein the annual rings are parallel.In another embodiment, the rings may be arranged at a varying angle tothe longitudinal axis, such that the annular rings are not parallel toeach other along the longitudinal axis of the implant.

FIG. 3A comprises a mold top portion 300 and a bottom portion 302. Thetop portion 300 and the bottom portion 302 may have an exterior 306 andinterior 308 surface. The interior 308 surface of both the top 300 andbottom 302 portions may be adapted to receive a shape memory polymermaterial. FIG. 3B illustrates the interior 308 surface of bottom portion302 of a mold The mold may comprise the inverse geometry of helicalrings 310. The rings may comprise a pattern of helical rings 310disposed about the mold interior 308 diagonally to the longitudinal axisof the mold. Rings 310 may comprise a depth 314, longitudinal distance316 and longitudinal separation distance 318. FIG. 3C illustrates, themold being an inverse of an implant, Helical rings may results in araised annular pattern 312. Of course, one skilled in the art willrecognized the pattern described can be varied by changing the depth314, longitudinal length 316 of the helical rings 310, or the spacing318 between each ring angle. Furthermore, the angle of the helix can bevaried to result in greater or lesser helical pitch. For example, theinverse helical pattern may be varied by altering the pitch angle of thespiral around the longitudinal axis of the implant. The angle may varyinfinitely from a very shallow slope, nearly orthogonal to thelongitudinal axis, to a very steep slope, i.e. nearly parallel to thelongitudinal axis. In addition, the spacing between the helical ringsmay be varied such that the number of helical spirals per unit oflongitudinal distance may be increased or decreased. Other variationsmay include altering the ring depth such that the raised helical patternextends from the implant wall to a varying degree.

FIG. 4A illustrates a mold top portion 400 and a bottom portion 402. Topportion 400 and bottom portion 402 may have an exterior 406 and interior408 surface. Interior 408 surface of both the top 400 and bottom 402portions may be adapted to receive a shape memory polymer material. FIG.4B illustrates an interior 408 surface of bottom portion 402 of a mold.Mold may have an inverse geometry of a mesh pattern. Mesh patternsurface may comprise a cross hatch of overlapped columns and row 410,which may be disposed along the length of the mold interior surface 408.As depicted in FIG. 4C, the mold is an inverse of the stent, the crosshatch of overlapped columns and row 410 results in a raised mesh pattern414 when the molding process is complete on the exterior of the stent.Of course one skilled in the art will recognized the pattern describedcan be varied by changing the angle or spacing between the rows andcolumn that form the mesh pattern.

For any of the raised patterns molded into the implant described above,alternate embodiment may be configured wherein the externally extendingraised patterns, such as for example, a textured surface, annular rings,helical rings and a mesh pattern may be limited to only a portion of theexterior surface of the implant. For example, the implant may have theexternally extending raised patterns limited longitudinally,circumferentially or in both directions.

More specifically, FIG. 5 illustrates the implant 104 wherein the raisedfeatures 500 may be placed around the entire circumference of theimplant, and within discrete longitudinal segments, such as only at theends of the implant or in a repeating interval pattern.

FIG. 6 illustrates another alternative, which may include placing theraised features along the entire longitudinal length of the implant andwithin discrete circumferential portions, such as having one or morelongitudinal discrete strips 502 of a raised feature from end to end andplaced at intervals around the circumference of the implant.

FIG. 7 illustrates another alternative, which may include placing theraised features along both discrete portions of the longitudinal lengthof the implant and within the discrete circumferential portions, such ashaving one or more longitudinal discrete sections of a raised featurepositioned in discontinuous sections along the implant and around thecircumference of the implant.

Stent 104 may be treated with a therapeutic agent or agents.“Therapeutic agents”, “pharmaceuticals,” “pharmaceutically activeagents”, “drugs” and other related terms may be used interchangeablyherein and include genetic therapeutic agents, non-genetic therapeuticagents and cells. Therapeutic agents may be used singly or incombination. A wide variety of therapeutic agents can be employed inconjunction with the present invention including those used for thetreatment of a wide variety of diseases and conditions (i.e., theprevention of a disease or condition, the reduction or elimination ofsymptoms associated with a disease or condition, or the substantial orcomplete elimination of a disease or condition).

Non-limiting examples of useful therapeutic agents include, but are notlimited to, adrenergic agents, adrenocortical steroids, adrenocorticalsuppressants, alcohol deterrents, aldosterone antagonists, amino acidsand proteins, ammonia detoxicants, anabolic agents, analeptic agents,analgesic agents, androgenic agents, anesthetic agents, anorecticcompounds, anorexic agents, antagonists, anterior pituitary activatorsand suppressants, anthelmintic agents, anti-adrenergic agents,anti-allergic agents, anti-amebic agents, anti-androgen agents,anti-anemic agents, anti-anginal agents, anti-anxiety agents,anti-arthritic agents, anti-asthmatic agents, anti-atheroscleroticagents, antibacterial agents, anticholelithic agents,anticholelithogenic agents, anticholinergic agents, anticoagulants,anticoccidal agents, anticonvulsants, antidepressants, antidiabeticagents, antidiuretics, antidotes, antidyskinetics agents, anti-emeticagents, anti-epileptic agents, anti-estrogen agents, antifibrinolyticagents, antifungal agents, antiglaucoma agents, antihemophilic agents,antihemophilic Factor, antihemorrhagic agents, antihistaminic agents,antihyperlipidemic agents, antihyperlipoproteinemic agents,antihypertensives, antihypotensives, anti-infective agents,anti-inflammatory agents, antikeratinizing agents, antimicrobial agents,antimigraine agents, antimitotic agents, antimycotic agents,antineoplastic agents, anti-cancer supplementary potentiating agents,antineutropenic agents, antiobsessional agents, antiparasitic agents,antiparkinsonian drugs, antipneumocystic agents, antiproliferativeagents, antiprostatic hypertrophydrugs, antiprotozoal agents,antipruritics, antipsoriatic agents, antipsychotics, antirheumaticagents, antischistosomal agents, antiseborrheic agents, antispasmodicagents, antithrombotic agents, antitussive agents, anti-ulcerativeagents, anti-urolithic agents, antiviral agents, benign prostatichyperplasia therapy agents, blood glucose regulators, bone resorptioninhibitors, bronchodilators, carbonic anhydrase inhibitors, cardiacdepressants, cardioprotectants, cardiotonic agents, cardiovascularagents, choleretic agents, cholinergic agents, cholinergic agonists,cholinesterase deactivators, coccidiostat agents, cognition adjuvantsand cognition enhancers, depressants, diagnostic aids, diuretics,dopaminergic agents, ectoparasiticides, emetic agents, enzymeinhibitors, estrogens, fibrinolytic agents, free oxygen radicalscavengers, gastrointestinal motility agents, glucocorticoids,gonad-stimulating principles, hemostatic agents, histamine H2 receptorantagonists, hormones, hypocholesterolemic agents, hypoglycemic agents,hypolipidemic agents, hypotensive agents, HMGCoA reductase inhibitors,immunizing agents, immunomodulators, immunoregulators, immunostimulants,immunosuppressants, impotence therapy adjuncts, keratolytic agents, LHRHagonists, luteolysin agents, mucolytics, mucosal protective agents,mydriatic agents, nasal decongestants, neuroleptic agents, neuromuscularblocking agents, neuroprotective agents, NMDA antagonists, non-hormonalsterol derivatives, oxytocic agents, plasminogen activators, plateletactivating factor antagonists, platelet aggregation inhibitors,post-stroke and post-head trauma treatments, progestins, prostaglandins,prostate growth inhibitors, prothyrotropin agents, psychotropic agents,radioactive agents, repartitioning agents, scabicides, sclerosingagents, sedatives, sedative-hypnotic agents, selective adenosine A1antagonists, adenosine A2 receptor antagonists (e.g., CGS 21680,regadenoson, UK 432097 or GW 328267), serotonin antagonists, serotonininhibitors, serotonin receptor antagonists, steroids, stimulants,thyroid hormones, thyroid inhibitors, thyromimetic agents,tranquilizers, unstable angina agents, uricosuric agents,vasoconstrictors, vasodilators, vulnerary agents, wound healing agents,xanthine oxidase inhibitors, and the like, and combinations thereof.

Useful non-genetic therapeutic agents for use in connection with thepresent invention include, but are not limited to,

-   (a) anti-thrombotic agents such as heparin, heparin derivatives,    urokinase, clopidogrel, and PPack (dextrophenylalanine proline    arginine chloromethylketone);-   (b) anti-inflammatory agents such as dexamethasone, prednisolone,    corticosterone, budesonide, estrogen, sulfasalazine and mesalamine;-   (c) antineoplastic/antiproliferative/anti-miotic agents such as    paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,    epothilones, endostatin, angiostatin, angiopeptin, monoclonal    antibodies capable of blocking smooth muscle cell proliferation, and    thymidine kinase inhibitors;-   (d) anesthetic agents such as lidocaine, bupivacaine and    ropivacaine;-   (e) anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an    RGD peptide-containing compound, heparin, hirudin, antithrombin    compounds, platelet receptor antagonists, anti-thrombin antibodies,    anti-platelet receptor antibodies, aspirin, prostaglandin    inhibitors, platelet inhibitors and tick antiplatelet peptides;-   (f) vascular cell growth promoters such as growth factors,    transcriptional activators, and translational promotors;-   (g) vascular cell growth inhibitors such as growth factor    inhibitors, growth factor receptor antagonists, transcriptional    repressors, translational repressors, replication inhibitors,    inhibitory antibodies, antibodies directed against growth factors,    bifunctional molecules consisting of a growth factor and a    cytotoxin, bifunctional molecules consisting of an antibody and a    cytotoxin;-   (h) protein kinase and tyrosine kinase inhibitors (e.g.,    tyrphostins, genistein, quinoxalines);-   (i) prostacyclin analogs;-   (j) cholesterol-lowering agents;-   (k) angiopoietins;-   (l) antimicrobial agents such as triclosan, cephalosporins,    aminoglycosides and nitrofurantoin;-   (m) cytotoxic agents, cytostatic agents and cell proliferation    affectors;-   (n) vasodilating agents;-   (o) agents that interfere with endogenous vasoactive mechanisms;-   (p) inhibitors of leukocyte recruitment, such as monoclonal    antibodies;-   (q) cytokines;-   (r) hormones;-   (s) inhibitors of HSP 90 protein (i.e., Heat Shock Protein, which is    a molecular chaperone or housekeeping protein and is needed for the    stability and function of other client proteins/signal transduction    proteins responsible for growth and survival of cells) including    geldanamycin;-   (t) smooth muscle relaxants such as alpha receptor antagonists    (e.g., doxazosin, tamsulosin, terazosin, prazosin and alfuzosin),    calcium channel blockers (e.g., verapimil, diltiazem, nifedipine,    nicardipine, nimodipine and bepridil), beta receptor agonists (e.g.,    dobutamine and salmeterol), beta receptor antagonists (e.g.,    atenolol, metaprolol and butoxamine), angiotensin-II receptor    antagonists (e.g., losartan, valsartan, irbesartan, candesartan,    eprosartan and telmisartan), and antispasmodic/anticholinergic drugs    (e.g., oxybutynin chloride, flavoxate, tolterodine, hyoscyamine    sulfate, diclomine);-   (u) bARKct inhibitors;-   (v) phospholamban inhibitors;-   (w) Serca 2 gene/protein;-   (x) immune response modifiers including aminoquizolines, for    instance, imidazoquinolines such as resiquimod and imiquimod;-   (y) human apolioproteins (e.g., AI, AII, AIII, AIV, AV, etc.);-   (z) selective estrogen receptor modulators (SERMs) such as    raloxifene, lasofoxifene, arzoxifene, miproxifene, ospemifene, PKS    3741, MF 101 and SR 16234;-   (aa) PPAR agonists, including PPAR-alpha, gamma and delta agonists,    such as rosiglitazone, pioglitazone, netoglitazone, fenofibrate,    bexaotene, metaglidasen, rivoglitazone and tesaglitazar;-   (bb) prostaglandin E agonists, including PGE2 agonists, such as    alprostadil or ONO 8815Ly;-   (cc) thrombin receptor activating peptide (TRAP);-   (dd) vasopeptidase inhibitors including benazepril, fosinopril,    lisinopril, quinapril, ramipril, imidapril, delapril, moexipril and    spirapril;-   (ee) thymosin beta 4;-   (ff) phospholipids including phosphorylcholine, phosphatidylinositol    and phosphatidylcholine; and-   (gg) VLA-4 antagonists and VCAM-1 antagonists.    The non-genetic therapeutic agents may be used individually or in    combination, including in combination with any of the agents    described herein.

Further examples of non-genetic therapeutic agents, not necessarilyexclusive of those listed above, include taxanes such as paclitaxel(including particulate forms thereof, for instance, protein-boundpaclitaxel particles such as albumin-bound paclitaxel nanoparticles,e.g., ABRAXANE), sirolimus, everolimus, tacrolimus, zotarolimus, Epo D,dexamethasone, estradiol, halofuginone, cilostazole, geldanamycin,alagebrium chloride (ALT-711), ABT-578 (Abbott Laboratories), trapidil,liprostin, Actinomcin D, Resten-NG, Ap-17, abciximab, clopidogrel,Ridogrel, beta-blockers, bARKct inhibitors, phospholamban inhibitors,Serca 2 gene/protein, imiquimod, human apolioproteins (e.g., AI-AV),growth factors (e.g., VEGF-2), as well derivatives of the forgoing,among others.

Useful genetic therapeutic agents for use in connection with the presentinvention include, but are not limited to, anti-sense DNA and RNA aswell as DNA coding for the various proteins (as well as the proteinsthemselves), such as (a) anti-sense RNA; (b) tRNA or rRNA to replacedefective or deficient endogenous molecules; (c) angiogenic and otherfactors including growth factors such as acidic and basic fibroblastgrowth factors, vascular endothelial growth factor, endothelialmitogenic growth factors, epidermal growth factor, transforming growthfactor α and β, platelet-derived endothelial growth factor,platelet-derived growth factor, tumor necrosis factor α, hepatocytegrowth factor and insulin-like growth factor; (d) cell cycle inhibitorsincluding CD inhibitors, and (e) thymidine kinase (“TK”) and otheragents useful for interfering with cell proliferation. DNA encoding forthe family of bone morphogenic proteins (“BMP's”) are also useful andinclude, but not limited to, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1),BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14,BMP-15, and BMP-16. Currently desirably BMP's are any of BMP-2, BMP-3,BMP-4, BMP-5, BMP-6 and BMP-7. These dimeric proteins can be provided ashomodimers, heterodimers, or combinations thereof, alone or togetherwith other molecules. Alternatively, or in addition, molecules capableof inducing an upstream or downstream effect of a BMP can be provided.Such molecules include any of the “hedgehog” proteins, or the DNA'sencoding them.

Vectors for delivery of genetic therapeutic agents include, but notlimited to, viral vectors such as adenoviruses, gutted adenoviruses,adeno-associated virus, retroviruses, alpha virus (Semliki Forest,Sindbis, etc.), lentiviruses, herpes simplex virus, replicationcompetent viruses (e.g., ONYX-015) and hybrid vectors; and non-viralvectors such as artificial chromosomes and mini-chromosomes, plasmid DNAvectors (e.g., pCOR), cationic polymers (e.g., polyethyleneimine,polyethyleneimine (PEI)), graft copolymers (e.g., polyether-PEI andpolyethylene oxide-PEI), neutral polymers such as polyvinylpyrrolidone(PVP), SP1017 (SLPRATEK), lipids such as cationic lipids, liposomes,lipoplexes, nanoparticles, or microparticles, with and without targetingsequences such as the protein transduction domain (PTD).

Cells for use in connection with the present invention may include cellsof human origin (autologous or allogeneic), including whole bone marrow,bone marrow derived mono-nuclear cells, progenitor cells (e.g.,endothelial progenitor cells), stem cells (e.g., mesenchymal,hematopoietic, neuronal), pluripotent stem cells, fibroblasts,myoblasts, satellite cells, pericytes, cardiomyocytes, skeletal myocytesor macrophage, or from an animal, bacterial or fungal source(xenogeneic), which can be genetically engineered, if desired, todeliver proteins of interest.

Numerous therapeutic agents, not necessarily exclusive of those listedabove, have been identified as candidates for vascular treatmentregimens, for example, as agents targeting restenosis (antirestenotics).Such agents are useful for the practice of the present invention andinclude one or more of the following:

-   (a) Ca-channel blockers including benzothiazapines such as diltiazem    and clentiazem, dihydropytidines such as nifedipine, amlodipine and    nicardapine, and phenylalkylamines such as verapamil;-   (b) serotonin pathway modulators including: 5-HT antagonists such as    ketanserin and naftidrofuryl, as well as 5-HT uptake inhibitors such    as fluoxetine;-   (c) cyclic nucleotide pathway agents including phosphodiesterase    inhibitors such as cilostazole and dipyridamole, adenylate/Guanylate    cyclase stimulants such as forskolin, as well as adenosine analogs;-   (d) catecholamine modulators including α-antagonists such as    prazosin and bunazosine, β-antagonists such as propranolol and    α/β-antagonists such as labetalol and carvedilol;-   (e) endothelin receptor antagonists such as bosentan, sitaxsentan    sodium, atrasentan, endonentan;-   (f) nitric oxide donors/releasing molecules including organic    nitrates/nitrites such as nitroglycerin, isosorbide dinitrate and    amyl nitrite, inorganic nitroso compounds such as sodium    nitroprusside, sydnonimines such as molsidomine and linsidomine,    nonoates such as diazenium diolates and NO adducts of    alkanediamines, S-nitroso compounds including low molecular weight    compounds (e.g., S-nitroso derivatives of captopril, glutathione and    N-acetyl penicillamine) and high molecular weight compounds (e.g.,    S-nitroso derivatives of proteins, peptides, oligosaccharides,    polysaccharides, synthetic polymers/oligomers and natural    polymers/oligomers), as well as C-nitroso-compounds,    O-nitroso-compounds, N-nitroso-compounds and L-arginine;-   (g) Angiotensin Converting Enzyme (ACE) inhibitors such as    cilazapril, fosinopril and enalapril;-   (h) ATII-receptor antagonists such as saralasin and losartin;-   (i) platelet adhesion inhibitors such as albumin and polyethylene    oxide;-   (j) platelet aggregation inhibitors including cilostazole, aspirin    and thienopyridine (ticlopidine, clopidogrel) and GP IIb/IIIa    inhibitors such as abciximab, epitifibatide and tirofiban;-   (k) coagulation pathway modulators including heparinoids such as    heparin, low molecular weight heparin, dextran sulfate and    β-cyclodextrin tetradecasulfate, thrombin inhibitors such as    hirudin, hirulog, PPACK(D-phe-L-propyl-L-arg-chloromethylketone) and    argatroban, FXa inhibitors such as antistatin and TAP (tick    anticoagulant peptide), Vitamin K inhibitors such as warfarin, as    well as activated protein C;-   (l) cyclooxygenase pathway inhibitors such as aspirin, ibuprofen,    flurbiprofen, indomethacin and sulfinpyrazone;-   (m) natural and synthetic corticosteroids such as dexamethasone,    prednisolone, methprednisolone and hydrocortisone;-   (n) lipoxygenase pathway inhibitors such as nordihydroguairetic acid    and caffeic acid;-   (o) leukotriene receptor antagonists; (p) antagonists of E- and    P-selectins;-   (q) inhibitors of VCAM-1 and ICAM-1 interactions;-   (r) prostaglandins and analogs thereof including prostaglandins such    as PGE1 and PGI2 and prostacyclin analogs such as ciprostene,    epoprostenol, carbacyclin, iloprost and beraprost;-   (s) macrophage activation preventers including bisphosphonates;-   (t) HMG-CoA reductase inhibitors such as lovastatin, pravastatin,    atorvastatin, fluvastatin, simvastatin and cerivastatin;-   (u) fish oils and omega-3-fatty acids;-   (v) free-radical scavengers/antioxidants such as probucol, vitamins    C and E, ebselen, trans-retinoic acid, SOD (orgotein) and SOD    mimics, verteporfin, rostaporfin, AGI 1067, and M 40419;-   (w) agents affecting various growth factors including FGF pathway    agents such as bFGF antibodies and chimeric fusion proteins, PDGF    receptor antagonists such as trapidil, IGF pathway agents including    somatostatin analogs such as angiopeptin and ocreotide, TGF-β    pathway agents such as polyanionic agents (heparin, fucoidin),    decorin, and TGF-β antibodies, EGF pathway agents such as EGF    antibodies, receptor antagonists and chimeric fusion proteins, TNF-α    pathway agents such as thalidomide and analogs thereof, Thromboxane    A2 (TXA2) pathway modulators such as sulotroban, vapiprost,    dazoxiben and ridogrel, as well as protein tyrosine kinase    inhibitors such as tyrphostin, genistein and quinoxaline    derivatives;-   (x) matrix metalloprotease (MMP) pathway inhibitors such as    marimastat, ilomastat, metastat, batimastat, pentosan polysulfate,    rebimastat, incyclinide, apratastat, PG 116800, RO 1130830 or ABT    518;-   (y) cell motility inhibitors such as cytochalasin B;-   (z) antiproliferative/antineoplastic agents including    antimetabolites such as purine antagonists/analogs (e.g.,    6-mercaptopurine and pro-drugs of 6-mercaptopurine such as    azathioprine or cladribine, which is a chlorinated purine nucleoside    analog), pyrimidine analogs (e.g., cytarabine and 5-fluorouracil)    and methotrexate, nitrogen mustards, alkyl sulfonates,    ethylenimines, antibiotics (e.g., daunorubicin, doxorubicin),    nitrosoureas, cisplatin, agents affecting microtubule dynamics    (e.g., vinblastine, vincristine, colchicine, Epo D, paclitaxel and    epothilone), caspase activators, proteasome inhibitors, angiogenesis    inhibitors (e.g., endostatin, angiostatin and squalamine), olimus    family drugs (e.g., sirolimus, everolimus, tacrolimus, zotarolimus,    etc.), cerivastatin, flavopiridol and suramin;-   (aa) matrix deposition/organization pathway inhibitors such as    halofuginone or other quinazolinone derivatives, pirfenidone and    tranilast;-   (bb) endothelialization facilitators such as VEGF and RGD peptide;-   (cc) blood rheology modulators such as pentoxifylline and-   (dd) glucose cross-link breakers such as alagebrium chloride    (ALT-711).    These therapeutic agents may be used individually or in combination,    including in combination with any of the agents described herein.

Numerous additional therapeutic agents useful for the practice of thepresent invention are also disclosed in U.S. Pat. No. 5,733,925 to Kunz,the contents of which is incorporated herein by reference.

A wide range of therapeutic agent loadings may used in connection withthe dosage forms of the present invention, with the pharmaceuticallyeffective amount being readily determined by those of ordinary skill inthe art and ultimately depending, for example, upon the condition to betreated, the nature of the therapeutic agent itself, the tissue intowhich the dosage form is introduced, and so forth.

As is readily apparent, numerous modifications and changes may readilyoccur to those skilled in the art, and hence it is not desired to limitthe invention to the a radially extendible stent for implantation in abodily passageway, being expandable from an initial unexpanded state toan expanded state a radially expandable stent exact constructionoperation as shown and described, and accordingly, all suitablemodification equivalents may be resorted to falling within the scope ofthe invention as claimed.

What is claimed is:
 1. A radially-expandable implant for implantation ina bodily passageway, said implant comprising a stent having a main bodyextending from an inside surface to an outside surface and from a firstend to a second end thereof, said main body comprising a shape-memorypolymer and being expandable from an initial unexpanded state to anexpanded state, wherein said outside surface of said main body is atextured non-textile outer surface defining an outwardly extendinggeometric pattern, wherein said pattern comprises a diagonal cross hatchpattern, the cross hatch pattern creates valleys including raisedregions, wherein the raised regions are pyramid-like regions between thevalleys.
 2. A radially-expandable implant as in claim 1, wherein saidshape memory polymer is selected from the group consisting ofpolynorbonene, polycaprolactone, polyenes, nylons, polycyclooctene(PCO), blends of PCO and styrene-butadiene rubber, polyvinylacetate/polyvinylidine fluoride (PVAc/PVDF), blends ofPVAc/PVDF/polymethylmethacrylate (PMMA), polyurethanes,styrene-butadiene copolymers, polyethylene, trans-isoprene, blends ofpolycaprolactone and n-butylacrylate, POSS polyurethane polymers andblends thereof.
 3. A radially-expandable implant as in claim 1, whereinsaid implant is pre-formed prior to implantation with said outwardlyextending geometric pattern.
 4. A radially-expandable implant as inclaim 1, wherein said outwardly extending geometric pattern extends in alongitudinal direction from said first end to said second end and aboutthe entire circumference of said implant.
 5. The radially-expandableimplant of claim 1, wherein the stent has a graft disposed on at least aportion of the outside surface thereof.
 6. The radially-expandableimplant of claim 3, wherein the stent has a graft disposed on at least aportion of the outside surface thereof.
 7. An implant for implantationin a bodily passageway, the implant comprising a radially-expandablesupport structure, the radially-expandable support structure having afirst layer extending from an interior surface to an exterior surface ofsaid support structure, the first layer comprising a shape-memorypolymer and being expandable from an initial unexpanded state to anexpanded state, wherein the exterior surface of the first layer is atextured non-textile outer surface defining an outwardly extendinggeometric pattern, wherein said pattern comprises a diagonal the crosshatch pattern creates valleys including raised regions, wherein theraised regions are pyramid-like regions between the valleys.
 8. Theimplant of claim 7 further comprising a graft disposed over at least aportion of the outside surface of the support structure.